Uncarboxylated matrix Gla-protein: A biomarker of vitamin K status and cardiovascular risk.

BACKGROUND: Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) is a biomarker of functional vitamin K status. High plasma dp-ucMGP concentrations reflect a low vitamin K status and have been related to vascular calcification. Our aims were to assess plasma levels of dp-ucMGP and their association with cardiovascular risk in a general population. METHODS: Plasma dp-ucMGP measurements were performed using the IDS-iSYS InaKtif MGP assay in 491 consecutive participants in a Danish general population study (229 males and 262 females, aged 19-71 years). Multivariable linear and logistic regressions were used to assess the association between dp-ucMGP levels and cardiovascular risk factors. RESULTS: Mean ± standard deviation (SD) for dp-ucMGP was 465 ± 181 pmol/L, and upper 95th percentile was 690 pmol/L. In logistic regression analyses, an increase in dp-ucMGP category (<300, 300-399, 400-499, ≥500 pmol/L) was positively associated with obesity, odds ratio (OR) 2.27 (95% confidence interval (CI) 1.54-3.33), history of cardiovascular disease, OR 1.77 (CI 1.02-3.05), and above-median estimated pulse wave velocity (ePWV), OR 1.54 (CI 1.21-1.96), when adjusted for age, sex, and lifestyle factors. 1 SD increase in diastolic and systolic blood pressure (BP) corresponded to a 5.5% (CI 2.9-8.0%) and 4.7% (CI 2.1-7.4%) increase in dp-ucMGP, respectively, when adjusted for age and sex. CONCLUSION: Plasma dp-ucMGP levels were positively associated with obesity, BP, ePWV, and history of cardiovascular disease. These findings support that dp-ucMGP is a biomarker of cardiovascular risk, and that vitamin K status could play a role in vascular calcification. The strong association with obesity deserves further attention.

Household dampness and microbial exposure related to allergy and respiratory health in Danish adults.

Background: Indoor dampness has consistently been associated with respiratory symptoms and exacerbations. The causal mechanisms may involve increased microbial exposures. However, the evidence regarding the influence of indoor microbial exposures under damp- and non-damp conditions on the risk of asthma and allergy has been inconclusive. Objective: The aim of this study was to investigate the association between dampness and microbial exposure with allergy and respiratory health in Danish adults using a cross-sectional design. Methods: From 1,866 participants of the Health2006 cohort, we selected three non-overlapping groups: 196 at random, 107 with confirmed atopy, and 99 without atopy. Bedroom dust was sampled using electrostatic dust fall collectors and analysed for endotoxin, ß-(1,3)-D-glucan, 19 microbial species or groups, and total fungal load. Household moisture-related problems and asthma were self-reported by questionnaire. Atopy was determined by skin-prick-testing and lung function was measured by spirometry. Results: Household moisture damage was positively associated with asthma outcomes, although this was statistically significant only in atopics for self-reported asthma (odds ratio (OR) 3.52; 95%CI 1.01-12.7). Mould odor was positively associated with wheezing (OR 6.05; 95%CI 1.19-30.7) in atopics. Inconsistent associations were found for individual microbial exposures and health outcomes. Inverse associations were observed between microbial diversity and rhinitis in the random sample and both doctor-diagnosed and self-reported asthma in non-atopics. Conclusions: In conclusion, our findings suggest that household moisture damage may increase the risk of asthma and wheeze with mould odor in atopics. In addition, asthma and allergy may be affected by the indoor microbial composition in urban domestic environments. Further studies are needed to identify and understand the causal agents and underlying mechanisms behind the potential effects of environmental microbial exposure on human health.

Identification of urine metabolites associated with 5-year changes in biomarkers of glucose homoeostasis.

AIM: Metabolomics provides information on pathogenetic mechanisms and targets for interventions, and may improve risk stratification. During the last decade, metabolomics studies were used to gain deeper insight into the pathogenesis of diabetes mellitus. However, longitudinal metabolomics studies of possible subclinical states of disturbed glucose metabolism are limited. Therefore, the aim of this study was to analyze the associations between baseline urinary metabolites and 5-year changes in continuous markers of glucose homoeostasis, including fasting glucose, HbA1c and homoeostasis model assessment of insulin resistance (HOMA-IR) index values. METHODS: Urine metabolites in 3986 participants at both baseline and 5-year follow-up of the population-based Inter99 study were analyzed by 1H-NMR spectroscopy. Linear regression and analyses of covariance models were used to detect associations between urine metabolites and 5-year changes in markers of glucose homoeostasis. RESULTS: Higher baseline levels of urinary alanine, betaine, N,N-dimethylglycine (DMG), creatinine and trimethylamine were associated with an increase in HbA1c from baseline to follow-up. In contrast, formic acid and trigonelline levels were associated with a decrease in HbA1c over time. Analyses of 5-year changes in fasting glucose and HOMA-IR index showed similar findings, with high baseline levels of lactic acid, beta-d-glucose, creatinine, alanine and 1-methylnicotinamide associated with increases in both parameters. CONCLUSION: Several urine metabolites were found to be associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis. The identified metabolites point to mechanisms involving betaine and coffee metabolism as well as the possible influence of the gut microbiome.

Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization.

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC). METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or ß-estimates with 95% confidence interval (CI). RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: ß=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: ß=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m2 higher BMI. CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

Hyperthyroxinemia is positively associated with prevalent and incident type 2 diabetes mellitus in two population-based samples from Northeast Germany and Denmark.

BACKGROUND AND AIMS: A potential causal relationship between thyroid function and type 2 diabetes mellitus is currently under debate, but the current state of research is limited. Our aim was to investigate the association of thyroid hormone levels with prevalent and incident type 2 diabetes mellitus (T2DM) in two representative studies. METHODS AND RESULTS: Analyses are based on data from the Study of Health in Pomerania (SHIP), a German population based cohort with 4308 individuals at baseline and 3300 individuals at a five-year follow-up, and from INTER99, a Danish population-based randomized controlled trial with 6784 individuals at baseline and 4516 individuals at the five-year-follow-up. Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentrations were measured in both studies, while free triiodothyronine was measured in SHIP only. T2DM was defined by self report or intake of anti-diabetic medication. Neither in SHIP nor in INTER99 we detected significant associations of serum TSH levels with prevalent or incident T2DM. Serum fT4 levels were significantly positively associated with prevalent T2DM in SHIP and INTER99. In longitudinal analyses baseline levels of fT4 were significantly positively associated with incident T2DM in SHIP (RR per pmol/L = 1.07; 95%-CI = 1.05-1.10), while this association barely missed statistical significance in INTER99 (RR per pmol/L = 1.03; 95%-CI = 0.99-1.06). In SHIP baseline fT3 levels were significantly associated with incident T2DM (RR per pmol/L = 1.21; 95%-CI = 1.16-1.27). CONCLUSION: We demonstrated positive associations of thyroid hormones with prevalent and incident type 2 diabetes mellitus suggesting that hyperthyroxinemia may contribute to the pathogenesis of this condition.

Association studies of genetic scores of serum vitamin B12 and folate levels with symptoms of depression and anxiety in two danish population studies.

BACKGROUND/OBJECTIVES: Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. Mendelian randomization studies are not subject to these limitations. The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety. SUBJECTS/METHODS: The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety. RESULTS: An increased weighed allele score for serum vitamin B12 was associated with decreased odds of a SCL-90-R score above the 90th percentile (OR 0.540 (95%CI 0.302-0.967)) in Health2006 but not in Inter99, in the pooled analysis (OR 0.817 (95%CI 0.331-2.018)) or with other outcomes. The weighed allele score for serum folate was not associated with any of the measured outcome variables: SCL-90-R scores of depression (pooled OR 0.603 (95%CI 0.101-3.602)), anxiety (pooled OR 0.619 (95%CI 0.110-3.495)), combined score or history of doctor-diagnosed depression or anxiety. CONCLUSION: Our results do not provide evidence for a causal effect of circulating folate or vitamin B12 on the risk of depression or anxiety. However, we cannot rule out small to moderate effects, and thus large scale studies are needed.

Predictive factors of self-reported hand eczema in adult Danes: a population-based cohort study with 5-year follow-up.

BACKGROUND: Information about predictive factors of hand eczema is crucial for primary prevention. OBJECTIVES: To investigate predictive factors of hand eczema in adult Danes from the general population. METHODS: Participants from a cross-sectional 5-year follow-up study in the general population, aged 18-72 years (n = 2270), completed questionnaires about skin health and were grouped into four hand eczema groups: 'never', 'incident', 'nonpersistent' and 'persistent'. Multiple logistic regression models adjusted for age group and sex were used to evaluate associations with baseline variables. The participation rate for the follow-up study was 66·5% (29·7% of the participants originally invited to the baseline study). RESULTS: A history of atopic dermatitis (AD) was associated with both persistent and incident hand eczema [odds ratio (OR) 9·0, 95% confidence interval (95% CI) 5·6-14·4 and OR 3·0, 95% CI 1·7-5·2, respectively]. Thus, even in adulthood, a history of AD should be considered as a predictor of incident hand eczema. While filaggrin gene (FLG) null mutations were not associated with incident hand eczema, a statistically significant association was observed with persistent hand eczema (OR 3·1, 95% CI 1·8-5·2). Finally, contact sensitization (23 allergens without nickel) was also associated with persistent hand eczema (OR 2·5, 95% CI 1·2-5·0), independently of a history of AD. CONCLUSIONS: This study confirms a history of AD as the strongest predictor of persistent hand eczema. We additionally found that a history of AD was associated with incident hand eczema in adults, in contrast to FLG mutations, which were associated only with persistent hand eczema in individuals with a history of AD, and not with incident hand eczema. Our study adds new knowledge to the interplay between AD, FLG mutations and hand eczema in the adult general population.

Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based studies.

BACKGROUND/OBJECTIVES: The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids. SUBJECTS/METHODS: The study included 12 532 adults from three population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes. RESULTS: GRSs for serum vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The ß coefficients (95% confidence interval (CI), P-value) for regression of log-transformed serum B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), P<0.001 and 0.85 (0.70, 1.01), P<0.01. No associations were observed between the vitamin B12 GRSs and any of the blood pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol concentrations (ß coefficient (95% CI, P-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), P=0.017), but not with blood pressure, triglyceride, and low-density lipoprotein and total cholesterol levels. CONCLUSIONS: GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists.

Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes.

BACKGROUND/OBJECTIVES: Vitamin D receptors and vitamin D-metabolising enzymes are present in the brain and in the central nervous system at sites responsible for the regulation of emotions and behaviour. This raises the hypothesis that low vitamin D is related to poor mental health. Our aim was to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and the self-reported symptoms and diagnosis of depression and anxiety in the adult general population. SUBJECTS/METHODS: Serum 25(OH)D was measured in three Danish population-based studies, including 5308 adults aged 18-64 years. After 5 years, 2004 participants were re-examined. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety was recorded by using a questionnaire. RESULTS: Serum 25(OH)D was not associated with SCL average scores for depression and anxiety when analysed by quantile median regression adjusted for sex, age and other potential confounders. The ß-coefficient and 95% confidence interval (CI) per 10 nmol/l serum 25(OH)D were 0.00 (-0.00 to 0.01) and P=0.23 for depression and -0.00 (-0.01 to 0.00) and P=0.19 for anxiety. Furthermore, no evidence of an association was observed with longitudinal changes (combining depression and anxiety score: ß (95% CI)=0.00 (-0.00 to 0.00), P=0.90), with scores >90 percentiles (odds ratio (OR) (95% CI)=1.02 (0.98-1.07), P=0.32), or with self-reported history (OR (95% CI)=1.02 (0.97-1.07), P=0.47) or incidence (OR (95% CI)=1.02 (0.92-1.12), P=0.77) of doctor-diagnosed depression and/or anxiety. CONCLUSIONS: Our results suggest that low serum 25(OH)D is not associated with self-reported symptoms/diagnosis of depression and anxiety.

No association between vitamin D and atopy, asthma, lung function or atopic dermatitis: a prospective study in adults.

Studies suggest that vitamin D may be involved in the pathogenesis of allergic disorders, asthma and decreased lung function. However, results are inconsistent and only few prospective studies have examined adults. The purpose of this study was to investigate the association of serum 25-hydroxy vitamin D (s25(OH)D) with atopy, atopic dermatitis (AD), asthma, wheezing and impaired lung function in a prospective study of Danish adults. A random sample of 3471 persons was examined in 2006-2008. Of these, 2308 were re-examined 5 years later. s25(OH)D and specific IgE against four common inhalant allergens were measured by standard procedures. Wheezing, asthma and AD were assessed from questionnaires and lung function was measured by spirometry. We found no statistically significant associations between s25(OH)D and prevalence or incidence of atopy, AD, asthma or wheezing. Associations with lung function were inconsistent. We conclude that vitamin D status does not influence these conditions in adults.

Adiposity measures and vitamin D concentrations in Northeast Germany and Denmark.

BACKGROUND: Body mass index (BMI) and serum 25-hydroxy vitamin D3 (25OHD) concentrations are inversely related. As BMI contains only limited information regarding body fat distribution, we aimed to analyze the cross-sectional associations of abdominal visceral or subcutaneous adipose tissue, next to common adiposity measures, with the 25OHD concentration. METHODS: Data were obtained from three cohorts of two large epidemiological studies in the northeast of Germany (Study of Health in Pomerania, SHIP-1 and SHIP-Trend), and in Denmark (Health2006). The study populations included adult men and women from the general population (N = 3072 SHIP-1, N = 803 SHIP-Trend, N = 3195 Health2006). Visceral and subcutaneous adipose tissue were quantified by magnetic resonance imagining (SHIP-Trend) or ultrasound (Health2006). Common adiposity measures, including BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio, body surface area, and body fat percentage were determined by standardized methods in SHIP-1 and Health2006. RESULTS: The average study participant was overweight (median BMI 27.4, 26.6, and 25.2 kg/m(2) in SHIP-1, SHIP-Trend, and Health2006, respectively). Visceral and subcutaneous adipose tissue as well as the common adiposity measures were inversely associated with serum 25OHD concentrations in linear regression models adjusted for age, sex, alcohol consumption, physical activity, smoking status, and month of blood sampling. CONCLUSIONS: Next to common adiposity measures, also abdominal visceral or subcutaneous adipose tissue are inversely associated with serum 25OHD concentrations in the general adult population.

Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations.

BACKGROUND: Epidermal filaggrin deficiency due to common filaggrin gene (FLG) mutations causes xerosis and strongly increases the risk of atopic dermatitis and even asthma. However, it is unknown whether xerosis independent of FLG mutations could also increase the risk of asthma. OBJECTIVE: To evaluate whether generalized xerosis was associated with asthma, independent of atopic dermatitis and common FLG mutations in a cross-sectional study on adult Danes. METHODS: A total of 3396 adults from the general population participated in a health examination. Lung function and serum-specific IgE levels to inhalant allergens were measured and information on xerosis and atopic diseases was obtained by means of a questionnaire. Participants were genotypes for the three most common FLG mutations in Northern Europeans: R501X, 2282del4 and R2447X. RESULTS: Fully adjusted logistic regression analyses showed that asthma (either current or at some point in life) was significantly associated with reporting generalized xerosis (OR 1.32; 95% CI 1.02-1.72). The association was stronger in men (OR 1.79; 95% CI 1.13-2.84) when compared to women (OR 1.18; 95% CI 0.86-1.62). Furthermore, a significant association was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). CONCLUSION: Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following T-helper cell 2 inflammation might be key elements to understanding this relationship.

The association of serum 25-OH vitamin D with atopy, asthma, and lung function in a prospective study of Danish adults.

BACKGROUND: Besides the important skeletal functions, it has been suggested that vitamin D is involved in the pathogenesis of allergy and asthma and related to lung function. However, previous studies are inconclusive. OBJECTIVE: The purpose of this study was to investigate associations of serum levels of 25-hydroxy vitamin D (25(OH)D) with atopy, asthma, and lung function in a prospective study of Danish adults. METHODS: This study included 4999 adults aged 30-60 years in 1999-2001. Three thousand and thirty-two of those included at baseline also participated at a follow-up examination 5 years later, and 3727 answered a 10-year follow-up questionnaire. Serum levels of (25(OH)D) were measured by high-performance liquid chromatography (HPLC) at baseline. No information on use of vitamin D supplements was available. Specific IgE against four common antigens was measured. Information about doctor-diagnosed asthma was obtained from questionnaires, and lung function (FEV1 and forced vital capacity) was measured by spirometry. RESULTS: We found no significant associations of 25(OH)D with atopy and doctor-diagnosed asthma. However, we found that low levels of 25(OH)D were associated with lower FEV1 percentage predicted (FEV1%pred) in the cross-sectional analyses. The odds ratio (OR) of FEV1%pred < 80% among participants in the highest quartile of 25(OH)D compared with those in the lowest was 0.66 (95% confidence interval (CI): 0.49-0.74). In contrast, prospective analyses indicated an association between high levels of 25(OH)D at baseline and adverse changes in lung function. OR (95%CI) of incident FEV1%pred < 80% was 1.73 (1.06-2.82) in the highest quartile of 25(OH)D compared with the lowest. CONCLUSIONS AND CLINICAL RELEVANCE: Our data indicates that 25(OH)D levels do not influence the development of asthma and allergy among adults. Further, the results did not consistently support that 25(OH)D levels associate with lung function. Randomized controlled trials are needed to further address this issue.

Atopy and cause-specific mortality.

BACKGROUND: Atopy is the familial or personal propensity to develop immunoglobulin E (IgE) antibodies against common environmental allergens and is associated with high risk of allergic disease. It has been proposed that atopy may have effects on risk of cardiovascular disease and cancer. OBJECTIVES: We investigated the association of atopy with all-cause and cause-specific mortality. METHODS: We included a total of 14 849 individuals from five Danish population-based cohorts with measurements of atopy defined as serum-specific IgE positivity against inhalant allergens. Participants were followed by linkage to the Danish Registry of Causes of Death to obtain information on mortality status and cause of death (median follow-up time 11.3 years). The relative mortality risk was estimated by Cox regression and expressed as hazard ratios, HRs (95% confidence intervals, CIs). RESULTS: A total of 1776 person died during follow-up. The mortality risk for atopics vs. non-atopics was: for all-cause mortality (HR = 1.03, 95% CI: 0.90, 1.17); neoplasms (HR = 0.86, 95% CI: 0.69, 1.06); endocrine, nutritional and metabolic disorders (HR = 1.48, 95% CI: 0.71, 3.08); mental and behavioural disorders (HR = 2.26, 95% CI: 1.18, 4.30); diseases of the nervous system (HR = 1.36, 95% CI: 0.65, 2.87); diseases of the circulatory system (HR = 1.00, 95% CI: 0.78, 1.29); diseases of the respiratory system (HR = 0.94, 95% CI: 0.55, 1.60); and diseases of the digestive system (HR = 1.75, 95% CI: 1.03, 2.98). CONCLUSIONS & CLINICAL RELEVANCE: We found no statistically significant association between atopy and all-cause mortality. However, atopy was associated with a significantly higher risk of dying from mental and behavioural disorders and gastrointestinal diseases, particularly liver diseases, and a lower risk of dying from breast cancer, but these associations were not statistically significant when applying the Bonferroni adjusted significance level. Further studies are needed to confirm our findings.

Filaggrin loss-of-function mutations and incident cancer: a population-based study.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. OBJECTIVES: To investigate the association of the FLG genotype and cancer types in four population-based cohorts. METHODS: A total of 13,376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. RESULTS: There were 1339 incident cancers (median follow-up 11·4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0·95, 95% CI 0·78-1·16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1·05, 95% CI 0·84-1·31), head and neck cancer (HR 1·72, 95% CI 0·71-4·15), colorectal cancer (HR 0·82, 95% CI 0·44-1·52), bronchus and lung cancer (HR 1·34, 95% CI 0·77-2·33), breast cancer (HR 0·58, 95% CI 0·30-1·14), uterine cancer (HR 0·42, 95% CI 0·06-3·10), prostate cancer (HR 1·09, 95% CI 0·61-1·94), urinary cancer (HR 1·30, 95% CI 0·51-3·29), malignant melanoma (HR 1·03, 95% CI 0·41-2·58) and NMSC (HR 0·70, 95% CI 0·47-1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. CONCLUSIONS: The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses.

Investigating the causal effect of vitamin D on serum adiponectin using a Mendelian randomization approach.

BACKGROUND/OBJECTIVES: The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian randomization approach. SUBJECTS/METHODS: Serum 25-hydroxy vitamin D (25(OH)D) and serum total or high molecular weight (HMW) adiponectin were measured in two Danish population-based studies: the Inter99 study (6405 adults, 30-60 years) conducted in 1999-2001, and the MONICA10 study (2656 adults, 41-71 years) conducted in 1993-1994. RESULTS: In the Inter99 study, serum 25(OH)D was positively associated with total adiponectin (the effect estimate in % per doubling of 25(OH)D was 4.78, 95% CI: 1.96, 7.68, P<0.001). Using variations in the vitamin D-binding protein gene and the filaggrin gene as instrumental variables, the causal effect in % was estimated to 61.46, 95% CI: 17.51, 120.28, P=0.003 higher adiponectin per doubling of 25(OH)D. In the MONICA10 cohort, no significant association was observed between the serum concentrations of 25(OH)D and HMW adiponectin (the effect estimate in % per doubling of 25(OH)D was -1.51, 95% CI: -5.80, 2.98, P=0.50), although the instrumental variables analysis to some extent supported a positive causal association (the effect estimate in % per doubling of 25(OH)D was 37.13, 95% CI: -3.67, 95.20, P=0.080). CONCLUSIONS: The results indicate a possible causal association between serum 25(OH)D and total adiponectin. However, the association was not replicated for HMW adiponectin. Thus, further studies are needed to confirm a causal relationship.

The relationship of serum triglycerides, serum HDL, and obesity to the risk of wheezing in 85,555 adults.

BACKGROUND: Asthma has been linked to obesity and the presence of the metabolic syndrome. OBJECTIVE: To explore which components of the metabolic syndrome that were associated with wheezing, a main symptom of asthma. Further, to explore whether these associations were different in individuals with and without rhinitis symptoms. METHODS: We used data from the Ibermutuamur Cardiovascular Risk Assessment Plan (ICARIA) including 85,555 Spanish workers (median age = 34, range = 16-75 years) with assessments of self reported wheezing and rhinitis symptoms. Fasting blood samples were analysed for serum triglyceride (s-TG), HDL (s-HDL) and glucose; blood pressure, waist circumference (WC) and body mass index (BMI) were measured. RESULTS: In mutually adjusted analyses including all components of the metabolic syndrome and possible confounders, elevated WC (or BMI), elevated s-TG and low s-HDL were significantly associated with wheezing. Odds ratio (OR) with confidence interval (CI) were: elevated WC = 1.54 (1.46-1.62), elevated s-TG = 1.24 (1.18-1.30), low s-HDL = 1.17 (1.12-1.22). These associations were stronger in individuals without than in those with rhinitis symptoms, OR's (CI's) were WC = without rhinitis 1.70 (1.57-1.85) vs. with rhinitis 1.47 (1.37-1.58). Elevated s-TG = without rhinitis 1.36 (1.26-1.46) vs. with rhinitis 1.21 (1.13-1.29). Low s-HDL = without rhinitis 1.24 (1.15-1.34) vs. with rhinitis 1.11 (1.04-1.18). CONCLUSIONS: High s-TG and low s-HDL were associated with wheezing after adjustment for adiposity. This may substantiate elevated s-TG and lowered s-HDL as markers or inducers of inflammation associated disease. The study supports the notion that these biochemical markers have differential effects on different types of wheezing.

Serum 25(OH)D and incident type 2 diabetes: a cohort study.

BACKGROUND/OBJECTIVES: Mild to moderate vitamin D insufficiency has been proposed as a risk factor for several common chronic diseases including type 2 diabetes. This study aimed to examine the association between serum 25-hydroxy vitamin D (25(OH)D) and incident diabetes. SUBJECTS/METHODS: The MONICA10 cohort consists of 2656 participants (men and women aged 41-71 years) who participated in a 10-year follow-up examination during 1993-1994 as part of the MONICA 1 population survey. A total of 2571 participants free of diabetes at baseline and with successful measurement of serum 25(OH)D were included in the current study. The Danish National Diabetes register enabled identification of 288 cases of incident diabetes during follow-up (median: 16.4 years). Data were analysed by Cox proportional hazard models and associations were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Serum 25(OH)D was inversely associated with incident diabetes adjusted for potential confounders (HR per 25 nmol/l=0.83; 95% CI: 0.72-0.95; P=0.009). A statistically significant interaction was observed between 25(OH)D and waist circumference (WC) (P(interaction)=0.042) suggesting an association in persons with a high WC (HR (95%CI) per 25 nmol/l=0.74 (0.63-0.88), 218 incident cases) and not in persons with a normal WC (HR (95%CI) per 25 nmol/l=0.98 (0.78-1.24), 70 incident cases). CONCLUSIONS: Low serum 25(OH)D was associated independently with incident diabetes. The inverse association was only found in overweight-obese and not in normal weight individuals, suggesting that obesity may modify the effect of vitamin D status on the risk of diabetes.

Determinants of vitamin D status in a general population of Danish adults.

BACKGROUND AND AIMS: Danish legislation regarding food fortification has been very restrictive and vitamin D deficiency is thought to be common in Denmark due to inadequate dietary intakes and the fact that in Denmark (latitude 56°N) vitamin D is only synthesized in the skin after exposure to solar radiation during summertime (April-September). The purpose of this study was to evaluate the vitamin D status of a general adult population in Denmark and, in addition, associations between vitamin D status and distinct lifestyle factors were studied. METHODS: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001. Serum samples from all participants were stored and levels of 25-hydroxyvitamin D (25(OH)D) were measured by HPLC in 2009. The method was compared to another HPLC method. Information on dietary intake of vitamin D and other lifestyle factors were obtained by questionnaires. A total of 6146 persons defined as ethnic Danes and with successful measurements of 25(OH)D were included in the analyses. RESULTS: The overall prevalence of vitamin D deficiency (25(OH)D<25 nmol/l) and insufficiency (25(OH)D<50 nmol/l) were 13.8% and 52.2%, respectively. A marked seasonal fluctuation was seen in serum levels of 25(OH)D - median values of 25(OH)D were lowest in February and highest in August. In multiple logistic regression models (n=5506), low vitamin D status was significantly associated with obesity (BMI≥30), daily smoking and a sedentary lifestyle. However, measurements of 25(OH)D were not associated with the estimated dietary intake of vitamin D. Comparison of two HPLC methods demonstrated considerable differences in accuracy. DISCUSSION AND CONCLUSIONS: Our results suggest that poor vitamin D status is common among adults in a Northern European country without food fortification with vitamin D. Methodological issues are, however, of great importance when using cut-off values to define poor vitamin D status. In addition, we demonstrated that low serum levels of 25(OH)D were associated with several lifestyle factors.

Atopy, asthma, and lung function in relation to folate and vitamin B(12) in adults.

BACKGROUND: Recent studies suggested low serum folate and impaired folate metabolism as potential risk factors for development of asthma and atopic disease, but the results are inconsistent. The aim of this study was to investigate the relations of markers of folate and vitamin B12 (B12) deficiency with different phenotypes of asthma and atopy. METHODS: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001, and 4516 (66.6%) of those also participated in a follow-up examination 5 years later. The examinations included spirometry, measurements of serum folate and B12, specific IgE to inhalant allergens, total IgE, and genotyping of the MTHFR-C677T polymorphism - a genetic marker of impaired folate metabolism. Information about dietary intake of folate and B12, asthma diagnosis, and airway symptoms was obtained by questionnaires. RESULTS: Low serum folate levels and the TT genotype of the MTHFR-C677T polymorphism were associated with increased prevalence of self-reported doctor-diagnosed asthma [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.05-1.79 and OR 1.52; 95% CI 1.12-2.06, respectively] and attacks of shortness of breath (OR 1.43, 95% CI 1.14-1.79 and OR 1.47; 95% CI: 1.14-1.91, respectively). We found no significant associations with lung function or atopic outcomes. Serum levels of B12 and dietary intake of folate and B12 were not associated with asthma or atopy. CONCLUSIONS: We found that two objective markers of folate deficiency were associated with self-reported doctor-diagnosed asthma and attacks of shortness of breath, but not with lung function or atopy.